Rare earth metal compositions for treating hyperphosphatemia and related methods

ABSTRACT

Rare earth metal compounds, particularly lanthanum, cerium, and yttrium, are formed as porous particles and are effective in binding metals, metal ions, and phosphate. A method of making the particles and a method of using the particles is disclosed. The particles may be used in the gastrointestinal tract or the bloodstream to remove phosphate or to treat hyperphosphatemia in mammals. The particles may also be used to remove metals from fluids such as water.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a DIVISIONAL patent application of U.S. patentapplication Ser. No. 11/181,650, with a filing date of Jul. 13, 2005,which is a CONTINUATION of Ser. No. 10/444,774, with a filing date ofMay 23, 2003, which claims the benefit of U.S. Provisional ApplicationSer. Nos. 60/396,989 (filed May 24, 2002), 60/403,868 (filed Aug. 14,2002), 60/430,284 (filed Dec. 2, 2002), and 60/461,175 (filed Apr. 8,2003), which are incorporated herein by reference in their entirety.

The present invention relates to rare earth metal compounds,particularly rare earth metal compounds having a porous structure. Thepresent invention also includes methods of making the porous rare earthmetal compounds and methods of using the compounds of the presentinvention. The compounds of the present invention can be used to bind orabsorb metals such as arsenic, selenium, antimony and metal ions such asarsenic III⁺ and V⁺. The compounds of the present invention maytherefore find use in water filters or other devices or methods toremove metals and metal ions from fluids, especially water.

The compounds of the present invention are also useful for binding orabsorbing anions such as phosphate in the gastrointestinal tract ofmammals. Accordingly, one use of the compounds of the present inventionis to treat high serum phosphate levels in patients with end-stage renaldisease undergoing kidney dialysis. In this aspect, the compounds may beprovided in a filter that is fluidically connected with a kidneydialysis machine such that the phosphate content in the blood is reducedafter passing through the filter.

In another aspect, the compounds can be used to deliver a lanthanum orother rare-earth metal compound that will bind phosphate present in thegut and prevent its transfer into the bloodstream. Compounds of thepresent invention can also be used to deliver drugs or to act as afilter or absorber in the gastrointestinal tract or in the blood stream.For example, the materials can be used to deliver inorganic chemicals inthe gastrointestinal tract or elsewhere.

It has been found that the porous particle structure and the highsurface area are beneficial to high absorption rates of anions.Advantageously, these properties permit the compounds of the presentinvention to be used to bind phosphate directly in a filtering devicefluidically connected with kidney dialysis equipment.

The use of rare earth hydrated oxides, particularly hydrated oxides ofLa, Ce, and Y to bind phosphate is disclosed in Japanese publishedpatent application 61-004529 (1986). Similarly, U.S. Pat. No. 5,968,976discloses a lanthanum carbonate hydrate to remove phosphate in thegastrointestinal tract and to treat hyperphosphatemia in patients withrenal failure. It also shows that hydrated lanthanum carbonates withabout 3 to 6 molecules of crystal water provide the highest removalrates. U.S. Pat. No. 6,322,895 discloses a form of silicon withmicron-sized or nano-sized pores that can be used to release drugsslowly in the body. U.S. Pat. No. 5,782,792 discloses a method for thetreatment of rheumatic arthritis where a “protein A immunoadsorbent” isplaced on silica or another inert binder in a cartridge to physicallyremove antibodies from the bloodstream.

It has now unexpectedly been found that the specific surface area ofcompounds according to the present invention as measured by the BETmethod, varies depending on the method of preparation, and has asignificant effect on the properties of the product. As a result, thespecific properties of the resulting compound can be adjusted by varyingone or more parameters in the method of making the compound. In thisregard, the compounds of the present invention have a BET specificsurface area of at least about 10 m²/g and may have a BET specificsurface area of at least about 20 m²/g and alternatively may have a BETspecific surface area of at least about 35 m²/g. In one embodiment, thecompounds have a BET specific surface area within the range of about 10m²/g and about 40 m²/g.

It has also been found that modifications in the preparation method ofthe rare earth compounds will create different entities, e.g. differentkinds of hydrated or amorphous oxycarbonates rather than carbonates, andthat these compounds have distinct and improved properties. It has alsobeen found that modifications of the preparation method create differentporous physical structures with improved properties.

The compounds of the present invention and in particular, the lanthanumcompounds and more particularly the lanthanum oxycarbonates of thepresent invention exhibit phosphate binding or removal of at least 40%of the initial concentration of phosphate after ten minutes. Desirably,the lanthanum compounds exhibit phosphate binding or removal of at least60% of the initial concentration of phosphate after ten minutes. Inother words, the lanthanum compounds and in particular, the lanthanumcompounds and more particularly the lanthanum oxycarbonates of thepresent invention exhibit a phosphate binding capacity of at least 45 mgof phosphate per gram of lanthanum compound. Suitably, the lanthanumcompounds exhibit a phosphate binding capacity of at least 50 mg PO₄/gof lanthanum compound, more suitably, a phosphate binding capacity of atleast 75 mg PO₄/g of lanthanum compound. Desirably, the lanthanumcompounds exhibit a phosphate binding capacity of at least 100 mg PO₄/gof lanthanum compound, more desirably, a phosphate binding capacity ofat least 110 mg PO₄/g of lanthanum compound.

In accordance with the present invention, rare earth metal compounds,and in particular, rare earth metal oxychlorides and oxycarbonates areprovided. The oxycarbonates may be hydrated or anhydrous. Thesecompounds may be produced according to the present invention asparticles having a porous structure. The rare earth metal compoundparticles of the present invention may conveniently be produced within acontrollable range of surface areas with resultant variable andcontrollable adsorption rates of ions.

The porous particles or porous structures of the present invention aremade of nano-sized to micron-sized crystals with controllable surfaceareas. The rare earth oxychloride is desirably lanthanum oxychloride(LaOCl). The rare earth oxycarbonate hydrate is desirably lanthanumoxycarbonate hydrate (La₂O(CO₃)₂.xH₂O where x is from and including 2 toand including 4). This compound will further be referred to in this textas La₂O(CO₃)₂.xH₂O. The anhydrous rare earth oxycarbonate is desirablylanthanum oxycarbonate La₂O₂CO₃ or La₂CO₅ of which several crystallineforms exist. The lower temperature form will be identified as La₂O₂CO₃and the form obtained at higher temperature or after a longercalcination time will be identified as La₂CO₅.

One skilled in the art, however, will understand that lanthanumoxycarbonate may be present as a mixture of the hydrate and theanhydrous form. In addition, the anhydrous lanthanum oxycarbonate may bepresent as a mixture of La₂O₂CO₃ and La₂CO₅ and may be present in morethan a single crystalline form.

One method of making the rare earth metal compound particles includesmaking a solution of rare earth metal chloride, subjecting the solutionto a substantially total evaporation process using a spray dryer orother suitable equipment to form an intermediate product, and calciningthe obtained intermediate product at a temperature between about 500°and about 1200° C. The product of the calcination step may be washed,filtered, and dried to make a suitable finished product. Optionally, theintermediate product may be milled in a horizontal or vertical pressuremedia mill to a desired surface area and then further spray dried ordried by other means to produce a powder that may be further washed andfiltered.

An alternative method of making the rare earth metal compounds,particularly rare earth metal anhydrous oxycarbonate particles includesmaking a solution of rare earth metal acetate, subjecting the solutionto a substantially total evaporation process using a spray dryer orother suitable equipment to make an intermediate product, and calciningthe obtained intermediate product at a temperature between about 400° C.and about 700° C. The product of the calcination step may be washed,filtered, and dried to make a suitable finished product. Optionally, theintermediate product may be milled in a horizontal or vertical pressuremedia mill to a desired surface area, spray dried or dried by othermeans to produce a powder that may be washed, filtered, and dried.

Yet another method of making the rare earth metal compounds includesmaking rare earth metal oxycarbonate hydrate particles. The rare earthmetal oxycarbonate hydrate particles can be made by successively makinga solution of rare earth chloride, subjecting the solution to a slow,steady feed of a sodium carbonate solution at a temperature betweenabout 30° and about 90° C. while mixing, then filtering and washing theprecipitate to form a filter cake, then drying the filter cake at atemperature of about 100° to 120° C. to produce the desired rare earthoxycarbonate hydrate species. Optionally, the filter cake may besequentially dried, slurried, and milled in a horizontal or verticalpressure media mill to a desired surface area, spray dried or dried byother means to produce a powder that may be washed, filtered, and dried.

Alternatively, the process for making rare earth metal oxycarbonatehydrate particles may be modified to produce anhydrous particles. Thismodification includes subjecting the dried filter cake to a thermaltreatment at a specified temperature between about 400° C. to about 700°C. and for a specified time between 1 h and 48 h. Optionally, theproduct of the thermal treatment may be slurried and milled in ahorizontal or vertical pressure media mill to a desired surface area,spray dried or dried by other means to produce a powder that may bewashed, filtered, and dried.

In accordance with the present invention, compounds of the presentinvention may be used to treat patients with hyperphosphatemia. Thecompounds may be made into a form that may be delivered to a mammal andthat may be used to remove phosphate from the gut or decrease phosphateabsorption into the blood stream. For example, the compounds may beformulated to provide an orally ingestible form such as a liquidsolution or suspension, a tablet, capsule, gelcap, or other suitable andknown oral form. Accordingly, the present invention contemplates amethod for treating hyperphosphatemia that comprises providing aneffective amount of a compound of the present invention. Compounds madeunder different conditions will correspond to different oxycarbonates oroxychlorides, will have different surface areas, and will showdifferences in reaction rates with phosphate and differentsolubilization of lanthanum or another rare-earth metal into the gut.The present invention allows one to modify these properties according tothe requirements of the treatment.

In another aspect of the present invention, compounds made according tothis invention as a porous structure of sufficient mechanical strengthmay be placed in a device fluidically connected to a dialysis machinethrough which the blood flows, to directly remove phosphate by reactionof the rare-earth compound with phosphate in the bloodstream. Thepresent invention therefore contemplates a device having an inlet and anoutlet with one or more compounds of the present invention disposedbetween the inlet and the outlet. The present invention alsocontemplates a method of reducing the amount of phosphate in blood thatcomprises contacting the blood with one or more compounds of the presentinvention for a time sufficient to reduce the amount of phosphate in theblood.

In yet another aspect of the present invention, the compounds of thepresent invention may be used as a substrate for a filter having aninlet and outlet such that the compounds of the present invention aredisposed between the inlet and the outlet. A fluid containing a metal,metal ion, phosphate or other ion may be passed from the inlet tocontact the compounds of the present invention and through the outlet.Accordingly, in one aspect of the present invention a method of reducingthe content of a metal in a fluid, for example water, comprises flowingthe fluid through a filter that contains one or more compounds of thepresent invention to reduce the amount of metal present in the water.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a general flow sheet of a process according to the presentinvention that produces LaOCl (lanthanum oxychloride).

FIG. 2 is a flow sheet of a process according to the present inventionthat produces a coated titanium dioxide structure.

FIG. 3 is a flow sheet of a process according to the present inventionthat produces lanthanum oxycarbonate

FIG. 4 is a graph showing the percentage of phosphate removed from asolution as a function of time by La₂O(CO₃)₂.x H₂O, (where x is from andincluding 2 to and including 4), made according to the process of thepresent invention, as compared to the percentage of phosphate removed bycommercial grade La carbonate La₂(CO₃)₃.4H₂O in the same conditions.

FIG. 5 is a graph showing the amount of phosphate removed from asolution as a function of time per g of a lanthanum compound used as adrug to treat hyperphosphatemia. The drug in one case is La₂O(CO₃)₂.xH₂O(where x is from and including 2 to and including 4), made according tothe process of the present invention. In the comparative case the drugis commercial grade La carbonate La₂(CO₃)₃.4H₂O.

FIG. 6 is a graph showing the amount of phosphate removed from asolution as a function of time per g of a lanthanum compound used as adrug to treat hyperphosphatemia. The drug in one case is La₂O₂CO₃ madeaccording to the process of the present invention. In the comparativecase the drug is commercial grade La carbonate La₂(CO₃)₃.4H₂O.

FIG. 7 is a graph showing the percentage of phosphate removed as afunction of time by La₂O₂CO₃ made according to the process of thepresent invention, as compared to the percentage of phosphate removed bycommercial grade La carbonate La₂(CO₃)₃.4H₂O.

FIG. 8 is a graph showing a relationship between the specific surfacearea of the oxycarbonates made following the process of the presentinvention and the amount of phosphate bound or removed from solution 10min after the addition of the oxycarbonate.

FIG. 9 is a graph showing a linear relationship between the specificsurface area of the oxycarbonates of this invention and the first orderrate constant calculated from the initial rate of reaction of phosphate.

FIG. 10 is a flow sheet of a process according to the present inventionthat produces lanthanum oxycarbonate hydrate La₂(CO₃)₂.xH₂O

FIG. 11 is a flow sheet of a process according to the present inventionthat produces anhydrous lanthanum oxycarbonate La₂O₂CO₃ or La₂CO₅.

FIG. 12 is a scanning electron micrograph of lanthanum oxychloride, madefollowing the process of the present invention.

FIG. 13 is an X-Ray diffraction scan of lanthanum oxychloride LaOCl madeaccording to the process of the present invention and compared with astandard library card of lanthanum oxychloride.

FIG. 14 is a graph showing the percentage of phosphate removed from asolution as a function of time by LaOCl made according to the process ofthe present invention, as compared to the amount of phosphate removed bycommercial grades of La carbonate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O inthe same conditions.

FIG. 15 shows a scanning electron micrograph of La₂O(CO₃)₂.xH₂O, where xis from and including 2 to and including 4.

FIG. 16 is an X-Ray diffraction scan of La₂O(CO₃)₂.xH₂O producedaccording to the present invention and includes a comparison with a“library standard” of La₂O(CO₃)₂.xH₂O where x is from and including 2 toand including 4.

FIG. 17 is a graph showing the rate of removal of phosphorous from asolution by La₂O(CO₃)₂.xH₂O compared to the rate obtained withcommercially available La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O in the sameconditions.

FIG. 18 is a scanning electron micrograph of anhydrous lanthanumoxycarbonate La₂O₂CO₃.

FIG. 19 is an X-Ray diffraction scan of anhydrous La₂O₂CO₃ producedaccording to the present invention and includes a comparison with a“library standard” of La₂O₂CO₃.

FIG. 20 is a graph showing the rate of phosphorous removal obtained withLa₂O₂CO₃ made following the process of the present invention andcompared to the rate obtained for commercially available La₂(CO₃)₃.4H₂Oand La₂(CO₃)₃.4H₂O.

FIG. 21 is a scanning electron micrograph of La₂CO₅ made according tothe process of the present invention.

FIG. 22 is an X-Ray diffraction scan of anhydrous La₂CO₅ producedaccording to the present invention and includes a comparison with alibrary standard” of La₂CO₅.

FIG. 23 is a graph showing the rate of phosphorous removal obtained withLa₂CO₅ made following the process of the present invention and comparedto the rate obtained for commercially available La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O.

FIG. 24 is a scanning electron micrograph of TiO₂ support material madeaccording to the process of the present invention.

FIG. 25 is a scanning electron micrograph of a TiO₂ structure coatedwith LaOCl, made according to the process of the present invention,calcined at 800° C.

FIG. 26 is a scanning electron micrograph of a TiO₂ structure coatedwith LaOCl, made according to the process of the present invention,calcined at 600° C.

FIG. 27 is a scanning electron micrograph of a TiO₂ structure coatedwith LaOCl, made according to the process of the present invention,calcined at 900° C.

FIG. 28 shows X-Ray scans for TiO₂ coated with LaOCl and calcined atdifferent temperatures following the process of the present invention,and compared to the X-Ray scan for pure LaOCl.

FIG. 29 shows the concentration of lanthanum in blood plasma as afunction of time, for dogs treated with lanthanum oxycarbonates madeaccording to the process of the present invention.

FIG. 30 shows the concentration of phosphorous in urine as a function oftime in rats treated with lanthanum oxycarbonates made according to theprocess of the present invention, and compared to phosphorusconcentration measured in untreated rats.

FIG. 31 shows a device having an inlet, an outlet, and one or morecompounds of the present invention disposed between the inlet and theoutlet.

DESCRIPTION OF THE INVENTION

Referring now to the drawings, the process of the present invention willbe described. While the description will generally refer to lanthanumcompounds, the use of lanthanum is merely for ease of description and isnot intended to limit the invention and claims solely to lanthanumcompounds. In fact, it is contemplated that the process and thecompounds described in the present specification is equally applicableto rare earth metals other than lanthanum such as Ce and Y.

Turning now to FIG. 1, a process for making a rare earth oxychloridecompound, and, in particular a lanthanum oxychloride compound accordingto one embodiment of the present invention is shown. First, a solutionof lanthanum chloride is provided. The source of lanthanum chloride maybe any suitable source and is not limited to any particular source. Onesource of lanthanum chloride solution is to dissolve commerciallanthanum chloride crystals in water or in an HCl solution. Anothersource is to dissolve lanthanum oxide in a hydrochloric acid solution.

The lanthanum chloride solution is evaporated to form an intermediateproduct. The evaporation 20 is conducted under conditions to achievesubstantially total evaporation. Desirably, the evaporation is conductedat a temperature higher than the boiling point of the feed solution(lanthanum chloride) but lower than the temperature where significantcrystal growth occurs. The resulting intermediate product may be anamorphous solid formed as a thin film or may have a spherical shape or ashape as part of a sphere.

The terms “substantially total evaporation” or “substantially completeevaporation” as used in the specification and claims refer toevaporation such that the resulting solid intermediate contains lessthan 15% free water, desirably less than 10% free water, and moredesirably less than 1% free water. The term “free water” is understoodand means water that is not chemically bound and can be removed byheating at a temperature below 150° C. After substantially totalevaporation or substantially complete evaporation, the intermediateproduct will have no visible moisture present.

The evaporation step may be conducted in a spray dryer. In this case,the intermediate product will consist of a structure of spheres or partsof spheres. The spray dryer generally operates at a dischargetemperature between about 120° C. and about 500° C.

The intermediate product may then be calcined in any suitablecalcination apparatus 30 by raising the temperature to a temperaturebetween about 500° C. to about 1200° C. for a period of time from about2 to about 24 h and then cooling to room temperature. The cooled productmay be washed 40 by immersing it in water or dilute acid, to remove anywater-soluble phase that may still be present after the calcination step30.

The temperature and the length of time of the calcination process may bevaried to adjust the particle size and the reactivity of the product.The particles resulting from calcination generally have a size between 1and 1000 μm. The calcined particles consist of individual crystals,bound together in a structure with good physical strength and a porousstructure. The individual crystals forming the particles generally havea size between 20 nm and 10 μm.

In accordance with another embodiment of the present invention as shownin FIG. 2, a feed solution of titanium chloride or titanium oxychlorideis provided by any suitable source. One source is to dissolve anhydroustitanium chloride in water or in a hydrochloric acid solution. Chemicalcontrol agents or additives 104 may be introduced to this feed solutionto influence the crystal form and the particle size of the finalproduct. One chemical additive is sodium phosphate Na₃PO₄. The feedsolution of titanium chloride or titanium oxychloride is mixed with theoptional chemical control agent 104 in a suitable mixing step 110. Themixing may be conducted using any suitable known mixer.

The feed solution is evaporated to form an intermediate product, whichin this instance is titanium dioxide (TiO₂). The evaporation 120 isconducted at a temperature higher than the boiling point of the feedsolution but lower than the temperature where significant crystal growthoccurs and to achieve substantially total evaporation. The resultingintermediate product may desirably be an amorphous solid formed as athin film and may have a spherical shape or a shape as part of a sphere.

The intermediate product may then be calcined in any suitablecalcination apparatus 130 by raising the temperature to a temperaturebetween about 400° C. to about 1200° C. for a period of time from about2 to about 24 h and then cooling to room temperature (25° C.). Thecooled product is then washed 140 by immersing it in water or diluteacid, to remove traces of any water-soluble phase that may still bepresent after the calcination step.

The method of manufacture of the intermediate product according to thepresent invention can be adjusted and chosen to make a structure withthe required particle size and porosity. For example, the evaporationstep 120 and the calcination step 130 can be adjusted for this purpose.The particle size and porosity can be adjusted to make the structure ofthe intermediate product suitable to be used as an inert filter in thebloodstream.

The washed TiO₂ product is then suspended or slurried in a solution ofan inorganic compound. A desirable inorganic compound is a rare-earth orlanthanum compound, and in particular lanthanum chloride. Thissuspension of TiO₂ in the inorganic compound solution is again subjectedto total evaporation 160 under conditions in the same range as definedin step 120 and to achieve substantially total evaporation. In thisregard, the evaporation steps 120 and 160 may be conducted in a spraydrier. The inorganic compound will precipitate as a salt, an oxide, oran oxy-salt. If the inorganic compound is lanthanum chloride, theprecipitated product will be lanthanum oxychloride. If the originalcompound is lanthanum acetate, the precipitated product will belanthanum oxide.

The product of step 160 is further calcined 170 at a temperature between500° and 1100° C. for a period of 2 to 24 h. The temperature and thetime of the calcination process influence the properties and theparticle size of the product. After the second calcination step 170, theproduct may be washed 180.

The resulting product can be described as crystals of lanthanumoxychloride or lanthanum oxide formed on a TiO₂ substrate. The resultingproduct may be in the form of hollow thin-film spheres or parts ofspheres. The spheres will have a size of about 1 μm to 1000 μm and willconsist of a structure of individual bound particles. The individualparticles have a size between 20 nm and 10 μm.

When the final product consists of crystals of lanthanum oxychloride ona TiO₂ substrate, these crystals may be hydrated. It has been found thatthis product will effectively react with phosphate and bind it as aninsoluble compound. It is believed that, if this final product isreleased in the human stomach and gastrointestinal tract, the productwill bind the phosphate that is present and decrease the transfer ofphosphate from the stomach and gastrointestinal tract to the bloodstream. Therefore, the product of this invention may be used to limitthe phosphorous content in the bloodstream of patients on kidneydialysis.

According to another embodiment of the present invention, a process formaking anhydrous lanthanum oxycarbonate is shown in FIG. 3. In thisprocess, a solution of lanthanum acetate is made by any method. Onemethod to make the lanthanum acetate solution is to dissolve commerciallanthanum acetate crystals in water or in an HCl solution.

The lanthanum acetate solution is evaporated to form an intermediateproduct. The evaporation 220 is conducted at a temperature higher thanthe boiling point of the lanthanum acetate solution but lower than thetemperature where significant crystal growth occurs and under conditionsto achieve substantially total evaporation. The resulting intermediateproduct may desirably be an amorphous solid formed as a thin film andmay have a spherical shape or a shape as part of a sphere.

The intermediate product may then be calcined in any suitablecalcination apparatus 230 by raising the temperature to a temperaturebetween about 400° C. to about 800° C. for a period of time from about 2to about 24 h and then cooled to room temperature. The cooled productmay be washed 240 by immersing it in water or dilute acid, to remove anywater-soluble phase that may still be present after the calcinationstep. The temperature and the length of time of the calcination processmay be varied to adjust the particle size and the reactivity of theproduct.

The particles resulting from the calcination generally have a sizebetween 1 and 1000 μm. The calcined particles consist of individualcrystals, bound together in a structure with good physical strength anda porous structure. The individual crystals generally have a sizebetween 20 nm and 10 μm.

The products made by methods shown in FIGS. 1, 2, and 3 comprise ceramicparticles with a porous structure. Individual particles are in themicron size range. The particles are composed of crystallites in thenano-size range, fused together to create a structure with good strengthand porosity.

The particles made according to the process of the present invention,have the following common properties:

-   -   a. They have low solubility in aqueous solutions, especially        serum and gastro-intestinal fluid, compared to non-ceramic        compounds.    -   b. Their hollow shape gives them a low bulk density compared to        solid particles. Lower density particles are less likely to        cause retention in the gastrointestinal tract.    -   c. They have good phosphate binding kinetics. The observed        kinetics are generally better than the commercial carbonate        hydrates La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. In the case of        lanthanum oxychloride, the relationship between the amount of        phosphate bound or absorbed and time tends to be closer to        linear than for commercial hydrated lanthanum carbonates. The        initial reaction rate is lower but does not significantly        decrease with time over an extended period. This behavior is        defined as linear or substantially linear binding kinetics. This        is probably an indication of more selective phosphate binding in        the presence of other anions.    -   d. Properties a, b, and c, above are expected to lead to less        gastrointestinal tract complications than existing products.    -   e. Because of their particular structure and low solubility, the        products of the present invention have the potential to be used        in a filtration device placed directly in the bloodstream.

Different lanthanum oxycarbonates have been prepared by differentmethods. It has been found that, depending on the method of preparation,lanthanum oxycarbonate compounds with widely different reaction ratesare obtained.

A desirable lanthanum oxycarbonate is La₂O(CO₃)₂.xH₂O, where 2≦x≦4. Thislanthanum oxycarbonate is preferred because it exhibits a relativelyhigh rate of removal of phosphate. To determine the reactivity of thelanthanum oxycarbonate compound with respect to phosphate, the followingprocedure was used. A stock solution containing 13.75 g/l of anhydrousNa₂HPO₄ and 8.5 g/l of HCl is prepared. The stock solution is adjustedto pH 3 by the addition of concentrated HCl. 100 ml of the stocksolution is placed in a beaker with a stirring bar. A sample oflanthanum oxycarbonate powder is added to the solution. The amount oflanthanum oxycarbonate powder is such that the amount of La insuspension is 3 times the stoichiometric amount needed to reactcompletely with the phosphate. Samples of the suspension are taken atintervals, through a filter that separated all solids from the liquid.The liquid sample is analyzed for phosphorous. FIG. 4 shows that after10 min, La₂O(CO₃)₂.H₂O has removed 86% of the phosphate in solution,whereas a commercial hydrated La carbonate La₂(CO₃)₃.4H₂O removes only38% of the phosphate in the same experimental conditions after the sametime.

FIG. 5 shows that the La₂O(CO₃)₂.xH₂O depicted in FIG. 4 has a capacityof phosphate removal of 110 mg PO₄ removed/g of La compound after 10 minin the conditions described above, compared to 45 mg PO₄/g for thecommercial La carbonate taken as reference.

Another preferred lanthanum carbonate is the anhydrous La oxycarbonateLa₂O₂CO₃. This compound is preferred because of its particularly highbinding capacity for phosphate, expressed as mg PO₄ removed/g ofcompound. FIG. 6 shows that La₂O₂CO₃ binds 120 mg PO₄/g of La compoundafter 10 min, whereas La₂(CO₃)₃.4H₂O used as reference only binds 45 mgPO₄/g La compound.

FIG. 7 shows the rate of reaction with phosphate of the oxycarbonateLa₂O₂CO₃. After 10 min of reaction, 73% of the phosphate had beenremoved, compared to 38% for commercial lanthanum carbonate used asreference.

Samples of different oxycarbonates have been made by different methodsas shown in Table 1 below.

TABLE 1 Example number Fraction of Initial corresponding to BET PO₄ 1storder manufacturing surface remaining rate constant Sample Compoundmethod area m²/g after 10 min k₁ (min⁻¹) 1 La₂O(CO₃)₂•xH₂O 11 41.3 0.1300.949 2 La₂O(CO₃)₂•xH2O 11 35.9 0.153 0.929 3 La₂O(CO₃)₂•xH₂O 11 38.80.171 0.837 4 La₂CO₅ (4 h milling) 7 25.6 0.275 0.545 5 La₂O₂CO₃ 5 180.278 0.483 6 La₂CO₅ (2 h milling) 7 18.8 0.308 0.391 7 La₂O₂CO₃ 7 16.50.237 0.36 8 La₂CO₅ (no milling) 5 11.9 0.483 0.434 9 La₂O(CO₃)₃•x4H₂Ocommercial sample 4.3 0.623 0.196 10 La₂O(CO₃)₃•x1H₂O commercial sample2.9 0.790 0.094

For each sample, the surface area measured by the BET method and thefraction of phosphate remaining after 10 min of reaction have beentabulated. The table also shows the rate constant k₁ corresponding tothe initial rate of reaction of phosphate, assuming the reaction isfirst order in phosphate concentration. The rate constant k₁ is definedby the following equation:

d[PO₄ ]/dt=−k ₁[PO₄]

where [PO₄] is the phosphate concentration in solution (mol/liter), t istime (min) and k₁ is the first order rate constant (min⁻¹). The tablegives the rate constant for the initial reaction rate, i.e. the rateconstant calculated from the experimental points for the first minute ofthe reaction.

FIG. 8 shows that there is a good correlation between the specificsurface area and the amount of phosphate reacted after 10 min. Itappears that in this series of tests, the most important factorinfluencing the rate of reaction is the surface area, independently ofthe composition of the oxycarbonate or the method of manufacture. A highsurface area can be achieved by adjusting the manufacturing method or bymilling a manufactured product.

FIG. 9 shows that a good correlation is obtained for the same compoundsby plotting the first order rate constant as given in Table I and theBET specific surface area. The correlation can be represented by astraight line going through the origin. In other words, withinexperimental error, the initial rate of reaction appears to beproportional to the phosphate concentration and also to the availablesurface area.

Without being bound by any theory, it is proposed that the observeddependence on surface area and phosphate concentration may be explainedby a nucleophilic attack of the phosphate ion on the La atom in theoxycarbonate, with resultant formation of lanthanum phosphate LaPO₄. Forexample, if the oxycarbonate is La₂O₂CO₃, the reaction will be:

½La₂O₂CO₃+PO₄ ³⁻+2H₂O→LaPO₄+½H₂CO₃+3OH⁻

If the rate is limited by the diffusion of the PO₄ ³⁻ ion to the surfaceof the oxycarbonate and the available area of oxycarbonate, the observedrelationship expressed in FIG. 9 can be explained. This mechanism doesnot require La to be present as a dissolved species. The presentreasoning also provides an explanation for the decrease of the reactionrate after the first minutes: the formation of lanthanum phosphate onthe surface of the oxycarbonate decreases the area available forreaction.

In general, data obtained at increasing pH show a decrease of thereaction rate. This may be explained by the decrease in concentration ofthe hydronium ion (H₃O⁺), which may catalyze the reaction byfacilitating the formation of the carbonic acid molecule from theoxycarbonate.

Turning now to FIG. 10, another process for making lanthanumoxycarbonate and in particular, lanthanum oxycarbonate tetra hydrate, isshown. First, an aqueous solution of lanthanum chloride is made by anymethod. One method to make the solution is to dissolve commerciallanthanum chloride crystals in water or in an HCl solution. Anothermethod to make the lanthanum chloride solution is to dissolve lanthanumoxide in a hydrochloric acid solution.

The LaCl₃ solution is placed in a well-stirred tank reactor. The LaCl₃solution is then heated to 80° C. A previously prepared analytical gradesodium carbonate is steadily added over a period of 2 hours withvigorous mixing. The mass of sodium carbonate required is calculated at6 moles of sodium carbonate per 2 moles of LaCl₃. When the required massof sodium carbonate solution is added, the resultant slurry orsuspension is allowed to cure for 2 hours at 80° C. The suspension isthen filtered and washed with demineralized water to produce a clearfiltrate. The filter cake is placed in a convection oven at 105° C. for2 hours or until a stable weight is observed. The initial pH of theLaCl₃ solution is 2, while the final pH of the suspension after cure is5.5. A white powder is produced. The resultant powder is a lanthanumoxycarbonate four hydrate (La₂O(CO₃)₂.xH₂O). The number of watermolecules in this compound is approximate and may vary between 2 and 4(and including 2 and 4).

Turning now to FIG. 11 another process for making anhydrous lanthanumoxycarbonate is shown. First, an aqueous solution of lanthanum chlorideis made by any method. One method to make the solution is to dissolvecommercial lanthanum chloride crystals in water or in an HCl solution.Another method to make the lanthanum chloride solution is to dissolvelanthanum oxide in a hydrochloric acid solution.

The LaCl₃ solution is placed in a well-stirred tank reactor. The LaCl₃solution is then heated to 80° C. A previously prepared analytical gradesodium carbonate is steadily added over 2 hours with vigorous mixing.The mass of sodium carbonate required is calculated at 6 moles of sodiumcarbonate per 2 moles of LaCl₃. When the required mass of sodiumcarbonate solution is added the resultant slurry or suspension isallowed to cure for 2 hours at 80° C. The suspension is then washed andfiltered removing NaCl (a byproduct of the reaction) to produce a clearfiltrate. The filter cake is placed in a convection oven at 105° C. for2 hours or until a stable weight is observed. The initial pH of theLaCl₃ solution is 2.2, while the final pH of the suspension after cureis 5.5. A white lanthanum oxycarbonate hydrate powder is produced. Nextthe lanthanum oxycarbonate hydrate is placed in an alumina tray, whichis placed in a high temperature muffle furnace. The white powder isheated to 500° C. and held at that temperature for 3 hours. AnhydrousLa₂C₂O₃ is formed.

Alternatively, the anhydrous lanthanum oxycarbonate formed as indicatedin the previous paragraph may be heated at 500° C. for 15 to 24 hinstead of 3 h or at 600° C. instead of 500° C. The resulting producthas the same chemical formula, but shows a different pattern in an X-Raydiffraction scan and exhibits a higher physical strength and a lowersurface area. The product corresponding to a higher temperature or alonger calcination time is defined here as La₂CO₅.

Turning now to FIG. 31, a device 500 having an inlet 502 and an outlet504 is shown. The device 500 may be in the form of a filter or othersuitable container. Disposed between the inlet 502 and the outlet 504 isa substrate 506 in the form of a plurality of one or more compounds ofthe present invention. The device may be fluidically connected to adialysis machine through which the blood flows, to directly removephosphate by reaction of the rare-earth compound with phosphate in thebloodstream. In this connection, the present invention also contemplatesa method of reducing the amount of phosphate in blood that comprisescontacting the blood with one or more compounds of the present inventionfor a time sufficient to reduce the amount of phosphate in the blood.

In yet another aspect of the present invention, the device 500 may beprovided in a fluid stream so that a fluid containing a metal, metalion, phosphate or other ion may be passed from the inlet 502 through thesubstrate 506 to contact the compounds of the present invention and outthe outlet 504. Accordingly, in one aspect of the present invention amethod of reducing the content of a metal in a fluid, for example water,comprises flowing the fluid through a device 500 that contains one ormore compounds of the present invention to reduce the amount of metalpresent in the water.

The following examples are meant to illustrate but not limit the presentinvention.

EXAMPLE 1

An aqueous solution containing 100 g/l of La as lanthanum chloride isinjected in a spray dryer with an outlet temperature of 250° C. Theintermediate product corresponding to the spray-drying step is recoveredin a bag filter. This intermediate product is calcined at 900° C. for 4hours. FIG. 12 shows a scanning electron micrograph of the product,enlarged 25,000 times. The micrograph shows a porous structure formed ofneedle-like particles. The X-Ray diffraction pattern of the product(FIG. 13) shows that it consists of lanthanum oxychloride LaOCl.

To determine the reactivity of the lanthanum compound with respect tophosphate, the following test was conducted. A stock solution containing13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl was prepared. Thestock solution was adjusted to pH 3 by the addition of concentrated HCl.An amount of 100 ml of the stock solution was placed in a beaker with astirring bar. The lanthanum oxychloride from above was added to thesolution to form a suspension. The amount of lanthanum oxychloride wassuch that the amount of La in suspension was 3 times the stoichiometricamount needed to react completely with the phosphate. Samples of thesuspension were taken at time intervals, through a filter that separatedall solids from the liquid. The liquid sample was analyzed forphosphorous. FIG. 14 shows the rate of phosphate removed from solution.

EXAMPLE 2 COMPARATIVE EXAMPLE

To determine the reactivity of a commercial lanthanum with respect tophosphate, the relevant portion of Example 1 was repeated under the sameconditions, except that commercial lanthanum carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O was used instead of the lanthanum oxychloride of thepresent invention. Additional curves on FIG. 14 show the rate of removalof phosphate corresponding to commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃).4H₂O. FIG. 14 shows that the rate of removalof phosphate with the commercial lanthanum carbonate is faster at thebeginning but slower after about 3 minutes.

EXAMPLE 3

An aqueous HCl solution having a volume of 334.75 ml and containingLaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % as La₂O₃ wasadded to a four liter beaker and heated to 80° C. with stirring. Theinitial pH of the LaCl₃ solution was 2.2. Two hundred and sixty five mlof an aqueous solution containing 63.59 g of sodium carbonate (Na₂CO₃)was metered into the heated beaker using a small pump at a steady flowrate for 2 hours. Using a Buchner filtering apparatus fitted with filterpaper, the filtrate was separated from the white powder product. Thefilter cake was mixed four times with 2 liters of distilled water andfiltered to wash away the NaCl formed during the reaction. The washedfilter cake was placed into a convection oven set at 105° C. for 2hours, or until a stable weight was observed. FIG. 15 shows a scanningelectron micrograph of the product, enlarged 120,000 times. Themicrograph shows the needle-like structure of the compound. The X-Raydiffraction pattern of the product (FIG. 16) shows that it consists ofhydrated lanthanum oxycarbonate hydrate (La₂O(CO₃)₂.H₂O), with 2≦x≦4.

To determine the reactivity of the lanthanum compound with respect tophosphate, the following test was conducted. A stock solution containing13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl was prepared. Thestock solution was adjusted to pH 3 by the addition of concentrated HCl.An amount of 100 ml of the stock solution was placed in a beaker with astirring bar. Lanthanum oxycarbonate hydrate powder made as describedabove was added to the solution. The amount of lanthanum oxycarbonatehydrate powder was such that the amount of La in suspension was 3 timesthe stoichiometric amount needed to react completely with the phosphate.Samples of the suspension were taken at time intervals through a filterthat separated all solids from the liquid. The liquid sample wasanalyzed for phosphorous. FIG. 17 shows the rate of phosphate removedfrom solution.

EXAMPLE 4 COMPARATIVE EXAMPLE

To determine the reactivity of a commercial lanthanum with respect tophosphate, the second part of Example 3 was repeated under the sameconditions, except that commercial lanthanum carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O was used instead of the lanthanum oxychloride of thepresent invention. FIG. 17 shows the rate of phosphate removed using thecommercial lanthanum carbonate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. FIG. 17shows that the rate of removal of phosphate with the lanthanumoxycarbonate is faster than with the commercial lanthanum carbonatehydrate (La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O).

EXAMPLE 5

An aqueous HCl solution having a volume of 334.75 ml and containingLaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % as La₂O₃ wasadded to a 4 liter beaker and heated to 80° C. with stirring. Theinitial pH of the LaCl₃ solution was 2.2. Two hundred and sixty five mlof an aqueous solution containing 63.59 g of sodium carbonate (Na₂CO₃)was metered into the heated beaker using a small pump at a steady flowrate for 2 hours. Using a Buchner filtering apparatus fitted with filterpaper the filtrate was separated from the white powder product. Thefilter cake was mixed four times with 2 liters of distilled water andfiltered to wash away the NaCl formed during the reaction. The washedfilter cake was placed into a convection oven set at 105° C. for 2 hoursuntil a stable weight was observed. Finally, the lanthanum oxycarbonatewas placed in an alumina tray in a muffle furnace. The furnacetemperature was ramped to 500° C. and held at that temperature for 3hours. The resultant product was determined to be anhydrous lanthanumoxycarbonate La₂O₂CO₃.

The process was repeated three times. In one case, the surface area ofthe white powder was determined to be 26.95 m²/gm. In the other twoinstances, the surface area and reaction rate is shown in Table 1. FIG.18 is a scanning electron micrograph of the structure, enlarged 60,000times. The micrograph shows that the structure in this compound is madeof equidimensional or approximately round particles of about 100 nm insize. FIG. 19 is an X-ray diffraction pattern showing that the productmade here is an anhydrous lanthanum oxycarbonate written as La₂O₂CO₃.

To determine the reactivity of this lanthanum compound with respect tophosphate, the following test was conducted. A stock solution containing13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl was prepared. Thestock solution was adjusted to pH 3 by the addition of concentrated HCl.An amount of 100 ml of the stock solution was placed in a beaker with astirring bar. Anhydrous lanthanum oxycarbonate made as described above,was added to the solution. The amount of anhydrous lanthanumoxycarbonate was such that the amount of La in suspension was 3 timesthe stoichiometric amount needed to react completely with the phosphate.Samples of the suspension were taken at intervals, through a filter thatseparated all solids from the liquid. The liquid sample was analyzed forphosphorous. FIG. 20 shows the rate of phosphate removed.

EXAMPLE 6 COMPARATIVE EXAMPLE

To determine the reactivity of a commercial lanthanum with respect tophosphate, the second part of Example 5 was repeated under the sameconditions, except that commercial lanthanum carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O was used instead of the La₂O₂CO₃ of the presentinvention. FIG. 20 shows the rate of removal of phosphate using thecommercial lanthanum carbonate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. FIG. 20shows that the rate of removal of phosphate with the anhydrous lanthanumoxycarbonate produced according to the process of the present inventionis faster than the rate observed with commercial lanthanum carbonatehydrate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

EXAMPLE 7

A solution containing 100 g/l of La as lanthanum acetate is injected ina spray-drier with an outlet temperature of 250° C. The intermediateproduct corresponding to the spray-drying step is recovered in a bagfilter. This intermediate product is calcined at 600° C. for 4 hours.FIG. 21 shows a scanning electron micrograph of the product, enlarged80,000 times. FIG. 22 shows the X-Ray diffraction pattern of the productand it shows that it consists of anhydrous lanthanum oxycarbonate. TheX-Ray pattern is different from the pattern corresponding to Example 5,even though the chemical composition of the compound is the same. Theformula for this compound is written as (La₂CO₅). Comparing FIGS. 21 and18 shows that the compound of the present example shows a structure ofleaves and needles as opposed to the round particles formed in Example5. The particles may be used in a device to directly remove phosphatefrom an aqueous or non-aqueous medium, e.g., the gut or the bloodstream.

To determine the reactivity of the lanthanum compound with respect tophosphate, the following test was conducted. A stock solution containing13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl was prepared. Thestock solution was adjusted to pH 3 by the addition of concentrated HCl.An amount of 100 ml of the stock solution was placed in a beaker with astirring bar. La₂CO₅ powder, made as described above, was added to thesolution. The amount of lanthanum oxycarbonate was such that the amountof La in suspension was 3 times the stoichiometric amount needed toreact completely with the phosphate. Samples of the suspension weretaken at intervals through a filter that separated all solids from theliquid. The liquid sample was analyzed for phosphorous. FIG. 23 showsthe rate of phosphate removed from solution.

EXAMPLE 8 COMPARATIVE EXAMPLE

To determine the reactivity of a commercial lanthanum with respect tophosphate commercial lanthanum carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O was used instead of the lanthanum oxycarbonate madeaccording to the present invention as described above. FIG. 23 shows therate of phosphate removal for the commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. FIG. 23 also shows that the rate ofphosphate removal with the lanthanum oxycarbonate is faster than therate of phosphate removal with commercial lanthanum carbonate hydrateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

EXAMPLE 9

To a solution of titanium chloride or oxychloride containing 120 g/l Tiand 450 g/l Cl is added the equivalent of 2.2 g/l of sodium phosphateNa₃PO₄. The solution is injected in a spray dryer with an outlettemperature of 250° C. The spray dryer product is calcined at 1050° C.for 4 h. The product is subjected to two washing steps in 2 molar HCland to two washing steps in water. FIG. 24 is a scanning electronmicrograph of the TiO₂ material obtained. It shows a porous structurewith individual particles of about 250 nm connected in a structure. Thisstructure shows good mechanical strength. This material can be used asan inert filtering material in a fluid stream such as blood.

EXAMPLE 10

The product of Example 9 is re-slurried into a solution of lanthanumchloride containing 100 g/l La. The slurry contains approximately 30%TiO₂ by weight. The slurry is spray dried in a spray dryer with anoutlet temperature of 250° C. The product of the spray drier is furthercalcined at 800° C. for 5 h. It consists of a porous TiO₂ structure witha coating of nano-sized lanthanum oxychloride. FIG. 25 is a scanningelectron micrograph of this coated product. The electron micrographshows that the TiO₂ particles are several microns in size. The LaOCl ispresent as a crystallized deposit with elongated crystals, often about 1μm long and 0.1 μm across, firmly attached to the TiO₂ catalyst supportsurface as a film of nano-size thickness. The LaOCl growth is controlledby the TiO₂ catalyst support structure. Orientation of rutile crystalsworks as a template for LaOCl crystal growth. The particle size of thedeposit can be varied from the nanometer to the micron range by varyingthe temperature of the second calcination step.

FIG. 26 is a scanning electron micrograph corresponding to calcinationat 600° C. instead of 800° C. It shows LaOCl particles that are smallerand less well attached to the TiO₂ substrate. FIG. 27 is a scanningelectron micrograph corresponding to calcination at 900° C. instead of800° C. The product is similar to the product made at 800° C., but theLaOCl deposit is present as somewhat larger crystals and more compactlayer coating the TiO₂ support crystals. FIG. 28 shows the X-Raydiffraction patterns corresponding to calcinations at 600°, 800° and900° C. The figure also shows the pattern corresponding to pure LaOCl.The peaks that do not appear in the pure LaOCl pattern correspond tofutile TiO₂. As the temperature increases, the peaks tend to becomehigher and narrower, showing that the crystal size of the LaOCl as wellas TiO₂ increases with the temperature.

EXAMPLE 11

An aqueous HCl solution having a volume of 334.75 ml and containingLaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % as La₂O₃ wasadded to a 4 liter beaker and heated to 80° C. with stirring. Theinitial pH of the LaCl₃ solution was 2.2. Two hundred and sixty five mlof an aqueous solution containing 63.59 g of sodium carbonate (Na₂CO₃)was metered into the heated beaker using a small pump at a steady flowrate for 2 hours. Using a Buchner filtering apparatus fitted with filterpaper the filtrate was separated from the white powder product. Thefilter cake was mixed four times, each with 2 liters of distilled waterand filtered to wash away the NaCl formed during the reaction. Thewashed filter cake was placed into a convection oven set at 105° C. for2 hours or until a stable weight was observed. The X-Ray diffractionpattern of the product shows that it consists of hydrated lanthanumoxycarbonate La₂O(CO₃)₂.xH₂O, where 2≦x≦4. The surface area of theproduct was determined by the BET method. The test was repeated 3 timesand slightly different surface areas and different reaction rates wereobtained as shown in Table 1.

EXAMPLE 12

Six adult beagle dogs were dosed orally with capsules of lanthanumoxycarbonate La₂O(CO₃)₂.xH₂O (compound A) or La₂O₂CO₃ (compound B) in across-over design using a dose of 2250 mg elemental lanthanum twicedaily (6 hours apart). The doses were administered 30 minutes afterprovision of food to the animals. At least 14 days washout was allowedbetween the crossover arms. Plasma was obtained pre-dose and 1.5, 3, 6,7.5, 9, 12, 24, 36, 48, 60, and 72 hours after dosing and analyzed forlanthanum using ICP-MS. Urine was collected by catheterization beforeand approximately 24 hours after dosing and creatinine and phosphorusconcentrations measured.

The tests led to reduction of urine phosphate excretion, a marker ofphosphorous binding. Values of phosphate excretion in urine are shown inTable 2 below.

TABLE 2 Median Phosphorus/creatinine ratio (% reduction La Oxycarbonatecompared to pre-dose compound value) 10^(th) and 90^(th) percentiles A48.4% 22.6-84.4% B 37.0% −4.1-63.1%Plasma lanthanum exposure: Overall plasma lanthanum exposure in the dogsis summarized in Table 3 below. The plasma concentration curves areshown in FIG. 29.

TABLE 3 Mean (sd) Area Under Maximum concentration La Oxycarbonate theCurve_(0-72 h) (ng · h/mL); C_(max) (ng/mL); (standard compound tested(standard deviation) deviation) A 54.6 (28.0) 2.77 (2.1) B 42.7 (34.8)2.45 (2.2)

EXAMPLE 13 First In Vivo Study in Rats

Groups of six adult Sprague-Dawley rats underwent 5/6th nephrectomy intwo stages over a period of 2 weeks and were then allowed to recover fora further two weeks prior to being randomized for treatment. The groupsreceived vehicle (0.5% w/v carboxymethyl cellulose), or lanthanumoxycarbonate A or B suspended in vehicle, once daily for 14 days by orallavage (10 ml/kg/day). The dose delivered 314 mg elementallanthanum/kg/day. Dosing was carried out immediately before the dark(feeding) cycle on each day. Urine samples (24 hours) were collectedprior to surgery, prior to the commencement of treatment, and twiceweekly during the treatment period. Volume and phosphorus concentrationwere measured.

Feeding—During the acclimatization and surgery period, the animals weregiven Teklad phosphate sufficient diet (0.5% Ca, 0.3% P; Teklad No.TD85343), ad libitum. At the beginning of the treatment period, animalswere pair fed based upon the average food consumption of thevehicle-treated animals the previous week.

5/6 Nephrectomy—After one week of acclimatization, all animals weresubjected to 5/6 nephrectomy surgery. The surgery was performed in twostages. First, the two lower branches of the left renal artery wereligated. One week later, a right nephrectomy was performed. Prior toeach surgery, animals were anesthetized with an intra-peritonealinjection of ketamine/xylazine mixture (Ketaject a 100 mg/ml andXylaject at 20 mg/ml) administered at 10 ml/kg. After each surgery, 0.25mg/kg Buprenorphine was administered for relief of post-surgical pain.After surgery, animals were allowed to stabilize for 2 weeks tobeginning treatment.

The results showing urine phosphorus excretion are given in FIG. 30. Theresults show a decrease in phosphorus excretion, a marker of dietaryphosphorus binding, after administration of the lanthanum oxycarbonate(at time >0), compared to untreated rats.

EXAMPLE 14 Second In Vivo Study in Rats

Six young adult male Sprague-Dawley rats were randomly assigned to eachgroup. Test items were lanthanum oxycarbonates La₂O₂CO₃ and La₂CO₅(compound B and compound C), each tested at 0.3 and 0.6% of diet. Therewas an additional negative control group receiving Sigmacell cellulosein place of the test item.

The test items were mixed thoroughly into Teklad 7012CM diet. All groupsreceived equivalent amounts of dietary nutrients.

Table 4 outlines the dietary composition of each group:

TABLE 4 Sigmacell Group ID Treatment Test Item cellulose Teklad Diet INegative 0.0% 1.2% 98.8% control II Compound B - 0.3% 0.9% 98.8% Midlevel III Compound B - 0.6% 0.6% 98.8% High level IV Compound C - 0.3%0.9% 98.8% Mid level V Compound C - 0.6% 0.6% 98.8% High level

Rats were maintained in the animal facility for at least five days priorto use, housed individually in stainless steel hanging cages. On thefirst day of testing, they were placed individually in metabolic cagesalong with their test diet. Every 24 hours, their output of urine andfeces was measured and collected and their general health visuallyassessed. The study continued for 4 days. Food consumption for each dayof the study was recorded. Starting and ending animal weights wererecorded.

Plasma samples were collected via retro-orbital bleeding from thecontrol (1) and high-dose oxycarbonate groups, III and V. The rats werethen euthanized with CO₂ in accordance with the IACUC study protocol.

Urine samples were assayed for phosphorus, calcium, and creatinineconcentration in a Hitachi 912 analyzer using Roche reagents. Urinaryexcretion of phosphorus per day was calculated for each rat from dailyurine volume and phosphorus concentration. No significant changes wereseen in animal weight, urine volume or creatinine excretion betweengroups. Food consumption was good for all groups.

Even though lanthanum dosage was relatively low compared to the amountof phosphate in the diet, phosphate excretion for 0.3 or 0.6% La addedto the diet decreased as shown in Table 5 below. Table 5 shows averagelevels of urinary phosphate over days 2, 3, and 4 of the test. Urinephosphorus excretion is a marker of dietary phosphorous binding.

TABLE 5 Urinary phosphate excretion (mg/day) Control 4.3 Compound B =La₂O₂CO₃ 2.3 Compound C = La₂CO₅ 1.9

EXAMPLE 15

Tests were run to determine the binding efficiency of eight differentcompounds for twenty-four different elements. The compounds tested aregiven in Table 6.

TABLE 6 Test ID Compound Preparation Technique 1 La₂O₃ Calcined thecommercial (Prochem) La₂(CO₃)₃•H₂O at 850° C. for 16 hrs. 2 La₂O₅Prepared by spray drying lanthanum acetate solution and calcining at600° C. for 7 hrs (method corresponding to FIG. 3) 3 LaOCl Prepared byspray drying lanthanum chloride solution and calcining at 700° C. for 10hrs (method corresponding to FIG. 1) 4 La₂(CO₃)₃•4H₂O Purchased fromProchem (comparative example) 5 Ti carbonate Made by the method of FIG.11, where the LaCl₃ solution is replaced by a TiOCl₂ solution. 6 TiO₂Made by the method corresponding to FIG. 2, with addition of sodiumchloride. 7 La₂(CO₃)₂•xH₂O Precipitation by adding sodium carbonatesolution to lanthanum chloride solution at 80° C. (Method correspondingto FIG. 10) 8 La₂O₂CO₃ Precipitation by adding sodium carbonate solutionto lanthanum chloride solution at 80° C. followed by calcination at 500°C. for 3 hrs. (Method of FIG. 11)

The main objective of the tests was to investigate the efficiency atwhich the compounds bind arsenic and selenium, in view of their use inremoving those elements from drinking water. Twenty-one different anionswere also included to explore further possibilities. The tests wereperformed as follows:

The compounds given in Table 6 were added to water and a spike and werevigorously shaken at room temperature for 18 hrs. The samples werefiltered and the filtrate analyzed for a suite of elements including Sb,As, Be, Cd, Ca, Cr, Co, Cu, Fe, Pb, Mg, Mn, Mo, Ni, Se, TI, Ti, V, Zn,Al, Ba, B, Ag, and P.

The spike solution was made as follows:

-   -   1. In a 500 ml volumetric cylinder add 400 ml of de-ionized        water.    -   2. Add standard solutions of the elements given above to make        solutions containing approximately 1 mg/l of each element.    -   3. Dilute to 500 mls with de-ionized water.

The tests were conducted as follows:

-   -   1. Weigh 0.50 g of each compound into its own 50 ml centrifuge        tube.    -   2. Add 30.0 ml of the spike solution to each.    -   3. Cap tightly and shake vigorously for 18 hrs.    -   4. Filter solution from each centrifuge tube through 0.2 μm        syringe filter. Obtain ˜6 ml of filtrate.    -   5. Dilute filtrates 5:10 with 2% HNO₃. Final Matrix is 1% HNO₃.    -   6. Submit for analysis.

The results of the tests are given in Table 7.

TABLE 7 % of the Analyte Removed Sb As Be Cd Ca Cr Co Cu Fe Pb Mg MnLa₂O₃ 89 85 97 95 21 100 69 89 92 92 0 94 La₂CO₅ 96 93 100 83 0 100 5297 100 99 0 99 LaOCl 86 76 89 46 0 100 28 88 100 99 0 28 La₂(CO₃)₃•4H₂O84 25 41 37 28 94 20 0 56 90 0 20 Ti(CO₃)₂ 96 93 100 100 99 99 99 98 10098 79 100 TiO₂ 96 93 8 4 0 6 0 11 49 97 0 1 La₂O(CO₃)₂•xH₂O 87 29 53 3728 100 20 10 58 98 0 25 La₂O₂CO₃ 97 92 100 85 21 100 59 98 100 99 0 99 %of the Analyte Removed Mo Ni Se Tl Ti V Zn Al Ba B Ag P La₂O₃ 89 28 72 890 95 95 85 23 0 47 96 La₂CO₅ 98 17 79 8 100 99 100 93 0 0 73 99 LaOCl94 0 71 13 100 99 24 92 7 0 96 96 La₂(CO₃)₃•4H₂O 98 1 78 5 100 99 16 1123 0 48 71 Ti(CO₃)₂ 91 98 97 96 24 100 100 92 100 0 99 98 TiO₂ 97 0 9762 0 86 0 0 0 30 99 66 La₂O(CO₃)₂•xH₂O 99 0 79 8 100 99 16 60 26 0 44 74La₂O₂CO₃ 99 34 81 12 100 99 100 92 23 0 87 99

The most efficient compounds for removing both arsenic and seleniumappear to be the titanium-based compounds 5 and 6. The lanthanumoxycarbonates made according to the process of the present inventionremove at least 90% of the arsenic. Their efficiency at removing Se isin the range 70 to 80%. Commercial lanthanum carbonate (4 in Table 6) isless effective.

The tests show that the lanthanum and titanium compounds made followingthe process of the present invention are also effective at removing Sb,Cr, Pb, Mo from solution. They also confirm the efficient removal ofphosphorus discussed in the previous examples.

While the invention has been described in conjunction with specificembodiments, it is to be understood that many alternatives,modifications, and variations will be apparent to those skilled in theart in light of the foregoing description. Accordingly, this inventionis intended to embrace all such alternatives, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. A method of treating hyperphosphatemia in a mammal, wherein the method comprises administering an effective amount of a composition comprising a rare earth metal compound to the mammal, and wherein the rare earth metal compound exhibits an X-Ray diffraction scan as shown in FIG. 16, and wherein the rare earth metal compound has a phosphate binding capacity of at least 50 mg PO₄/g of rare earth metal compound.
 2. The method according to claim 1, wherein the rare earth metal compound comprises particles, and wherein the particles are between 1 and 1000 μm in size.
 3. The method according to claim 1, wherein the rare earth metal compound has a phosphate binding capacity of at least 75 mg PO₄/g of rare earth metal compound.
 4. The method according to claim 1, wherein the rare earth metal compound has a BET specific surface area of at least about 10 m²/g.
 5. The method according to claim 1, wherein the rare earth metal compound is hydrated.
 6. The method according to claim 2, wherein the particles comprise individual crystals.
 7. The method according to claim 6, wherein the rare earth metal compound has a phosphate binding capacity of at least 75 mg PO₄/g of rare earth metal compound.
 8. The method according to claim 7, wherein the rare earth metal compound has a BET specific surface area of at least about 10 m²/g.
 9. The method according to claim 8, wherein the rare earth metal compound has a phosphate binding capacity of at least 100 mg PO₄/g of rare earth metal compound.
 10. The method according to claim 8, wherein the individual crystals are between 20 nm and 10 μm in size. 